DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Application
Claims 1-15 are pending as of the response filed 12/18/2025. Claims 1-15 are examined herein.
Applicant’s submission of a declaration under 37 C.F.R. 1.132; and MPEP 716.10 dated 12/18/2025 is acknowledged. Applicants declaration submitted indicates that the Lim reference is a grace period intervening disclosure by third party, directly obtained from the inventor (Lee et al. publication) (Pgs. 1-2 of the declaration dated 12/18/2025). Therefore, the Lim reference is excepted as prior art under 35 U.S.C. 102(b)(1)(B) exception.
Applicant’s arguments have been fully considered and were found to be persuasive.
The 35 U.S.C. 103 rejection of previous record is hereby withdrawn in consideration of the declaration and Applicant’s arguments.
The nonstatutory double patenting rejection of record is maintained.
In view of the pending claims, new objections and rejections are made, as discussed below. Since these rejections are not necessitated by amendments, this Office action is non-final.
Claim Objections
Claims 1-2 and 5-9 are objected to because of the following informalities:
In claim 1, it is suggested to amend the claim as follows “A method for treating and/or preventing dilated cardiomyopathy due to an LMNA mutation in a subject, the method comprising:
administering to [[a]]the subject a therapeutically effective amount of an inhibitor of PDGF signaling”.
In claim 2, it is suggested to amend the claim as follows “A method for treating and/or preventing dilated cardiomyopathy due to an LMNA mutation in a subject, the method comprising:
administering to [[a]]the subject a therapeutically effective amount of crenolanib or salt thereof”.
In claims 5-9, it is suggested to amend the claims to recite “wherein the therapeutically effective amount”, for consistency of claim language.
Appropriate correction is required.
Claim Rejections - 35 USC § 103 - New
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-2 and 4-15 are rejected under 35 U.S.C. 103 as being unpatentable over the combined teachings of Fang et al. (WO 2019/233469 A1, publication date 12 December 2019, hereinafter Fang in the IDS – citations are based on attached WIPO English translation), Tintelen et al. (Severe Myocardial Fibrosis Caused by a Deletion of the 5’ End of the Lamin A/C Gene, 26 June 2007, hereinafter Tintelen) and Makino et al. (Blockade of PDGF Receptors by Crenolanib Has Therapeutic Effect in Patient Fibroblasts and in Preclinical Models of Systemic Sclerosis, 27 May 2017, hereinafter Makino in the IDS).
Examiner’s note : A new translated version of the Fang reference is reattached with this Office action.
Regarding instant claims 1-2, Fang relates to the use of a PDGFR signaling pathway inhibitor in the treatment of diseases (Para. [0001]). Fang teaches a method of treating and/or preventing a disease by administering an effective amount of crenolanib or a pharmaceutically acceptable salt thereof to a patient (Para. [0076]; Claim 13; Paras. [0051]-[0052]). Fang teaches “treatment” refers to relieving symptoms, temporarily or permanently eliminating the cause of the symptoms, or preventing or slowing the manifestation of a specified disease or condition (Para. [0115]). Fang teaches PDGFR signaling pathway plays an important role in embryonic development and maintenance of environmental homeostasis in the human body, but excessive expression of PDGFR signaling pathway is related to various diseases, including various fibrotic diseases, such as those associated with the heart and systemic sclerosis (Para. [0010]).
Fang do not teach treating and/or preventing dilated cardiomyopathy due to an LMNA mutation.
Tintelen teaches mutations in the LMNA gene (encoding lamin A/C proteins) as the major genetic cause of dilated cardiomyopathy (DCM) (Pg. 2430, second column, second full paragraph). Tintelen teaches myocardial fibrosis accompanies virtually all forms of cardiomyopathy (Pg. 2430, second column, last paragraph). Tintelen teaches myocardial fibrosis occurs at the first signs of conduction delay in majority of those having DCM due to LMNA gene mutations (Pg. 2436, first column, last paragraph – second column, continued paragraph; Pg. 2438, first column, first full paragraph). Tintelen teaches that LMNA mutations give rise to a type of cardiomyopathy in which primary fibrosis drives the specific pathophysiology on a highly malignant course (Pg. 2438, second column, continued paragraph; Pg. 2348, first column, continued paragraph).
Makino teaches crenolanib, an inhibitor of PDGF receptor signaling, attenuated heart fibrosis, in vivo, in a mouse model of heart fibrosis (Abstract; Pg. 1675, first column, third full paragraph; Figure 6). Makino teaches crenolanib to have shown a good safety profile in clinical trials (Pg. 1677, second column, first full paragraph).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, in view of the teachings of Fang, Tintelen and Makino, to have modified the method of Fang to treat a patient afflicted with dilated cardiomyopathy due to an LMNA mutation, to arrive at the method of the instant claims with a reasonable expectation of success. Fang teaches a method of treating and/or preventing a disease by administering an effective amount of a PDGFR signaling pathway inhibitor, crenolanib or a pharmaceutically acceptable salt thereof, to a patient. Fang teaches excessive expression of PDGFR signaling pathway is related to various diseases, including various fibrotic diseases, such as those associated with the heart. Tintelen teaches mutations in the LMNA gene (encoding lamin A/C proteins) as the major genetic cause of dilated cardiomyopathy (DCM). Tintelen teaches myocardial fibrosis accompanies virtually all forms of cardiomyopathy and occurs at the first signs of conduction delay in majority of those having DCM due to a LMNA mutation. Tintelen teaches that LMNA mutations give rise to a type of cardiomyopathy in which primary fibrosis drives the specific pathophysiology on a highly malignant course. Makino teaches crenolanib, an inhibitor of PDGF receptor signaling, attenuated heart fibrosis.
Therefore, one of ordinary skill in the art would have been motivated to apply the method of Fang that results in the inhibition of PDGF signaling, in the treatment or prevention of dilated cardiomyopathy due to an LMNA mutation, with a reasonable expectation of success in treating such a condition. The motivation being to prevent fibrotic damage that accompanies overexpression of PDGFR signaling, thereby rescuing a severe clinical outcome (Fang, Para. [0010]; Tintelen, Pg. 2438, second column, continued paragraph).
Regarding instant claims 11-12, the combined teachings of Fang, Tintelen and Makino render the method of instant claim 1, prima facie obvious. Fang teaches the PDGFR signaling inhibitor is administered orally, intravenously, intramuscularly, intraarterially, intramedullarily, intrathecally, intraventricular, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual or rectal administration (Para. [0074]; Claim 12) (this renders both systemically delivered as well as locally delivered routes as in instant claim 11-12 prima facie obvious).
Regarding instant claim 13, the combined teachings of Fang, Tintelen and Makino render the method of instant claim 1, prima facie obvious. Fang teaches crenolanib was administered twice on the second and fourth day of therapy (Para. [0189]). Fang teaches the exact dosage will be determined by the physician based on factors related to the subject in need of treatment (Para. [0075]). Fang do not teach wherein the inhibitor of PDGF signaling is administered up to three times a day for as long as the subject is in need of a treatment for cardiovascular disease.
According to MPEP 2144.05(II)(A), "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Therefore, it would have taken no more than the relative skills of
one of ordinary skill in the art through routine experimentation to have arrived at the
optimal administration schedule and duration of treatment, absent any criticality of the times of administration. The optimal dosing would have been made taking into consideration a variety of factors, such as the age, weight, sex, diet, severity of the medical condition of the patient and pharmacological considerations, such as activity, efficacy, pharmacokinetics and toxicology profiles. This is well within the skill of a person of ordinary skill in the pharmaceutical arts.
Regarding instant claim 15, the combined teachings of Fang, Tintelen and Makino render the method of instant claim 1, prima facie obvious. Fang teaches a small molecule inhibitor is selected from the group consisting of: Imatinib, Axitinib, Sorafenib, Sunitinib, Ponatinib (AP24534), Pazopanib, or one of its derivatives having PDGFR signaling pathway inhibitory properties, pharmaceutically acceptable salts, thereof (Paras. [[0049]-[0050]). Therefore, the limitations of instant claim 15 are rendered prima facie obvious.
Regarding instant claims 10 and 14, the combined teachings of Fang, Tintelen and Makino render the method of instant claim 2, prima facie obvious. Fang teaches the administration of 50 mg to 500 mg per day, 100 to 450 mg per day, 200 to 400 mg per day, 300 to 500 mg per day, 350 to 500 mg per day, or 400 to 500 mg per day of crenolanib (Para. [0077]; Claim 13). Fang teaches suitable pharmaceutically acceptable salts to include inorganic and organic acid addition salts such as hydrochloride, phosphate, acetate, citrate, p-toluenesulfonate (Para. [0117]). Therefore, the limitations of instant claims 10 and 14 are rendered prima facie obvious.
Regarding instant claims 4-9, the combined teachings of Fang, Tintelen and Makino render the method of instant claim 2, prima facie obvious.
Fang, Tintelen and Makino do not teach wherein the effective amount of crenolanib or salt thereof prevents or reduces LMNA-mediated hyperactivation of PDGFRβ in cardiomyocyte; wherein LMNA-mediated hyperactivation of PDGFRβ signaling pathways in cardiomyocytes leads to changes in gene and protein expression to exhibit a proarrhythmic phenotype; wherein the effective amount of crenolanib or salt thereof reduces the level of phosphorylation of CAMK2D and RYR2; wherein the effective amount of crenolanib or salt thereof prevents or reduces the pro-arrhythmic phenotype of cardiomyocytes carrying an LMNA mutation; wherein the effective amount of crenolanib or salt thereof downregulates genes associated with muscle contraction and regulation of cardiac conduction; wherein the effective amount of crenolanib or salt thereof prevents and/or treats systolic and/or diastolic dysfunction associated with LMNA mutation.
However, these limitations are related to the mechanism of action of the agent, crenolanib (an inhibitor of PDGF signaling), in the treatment. The combined teachings of Fang, Tintelen and Makino, teaches the active step of administering the same agent (crenolanib or salt thereof), to the same patient population (a subject afflicted with dilated cardiomyopathy due to an LMNA mutation), in the same effective amounts (50 mg to 500 mg per day, 100 to 450 mg per day, 200 to 400 mg per day, 300 to 500 mg per day, 350 to 500 mg per day, or 400 to 500 mg per day of crenolanib). In the absence of evidence to the contrary, the method of Fang, when practiced in treating a subject with dilated cardiomyopathy due to an LMNA mutation, would have necessarily produced the same treatment effects. Therefore, the limitations of instant claims 4-9 are held unpatentable.
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over the combined teachings of Fang et al. (WO 2019/233469 A1, publication date 12 December 2019, hereinafter Fang in the IDS – citations are based on attached WIPO English translation), Tintelen et al. (Severe Myocardial Fibrosis Caused by a Deletion of the 5’ End of the Lamin A/C Gene, 26 June 2007, hereinafter Tintelen) and Makino et al. (Blockade of PDGF Receptors by Crenolanib Has Therapeutic Effect in Patient Fibroblasts and in Preclinical Models of Systemic Sclerosis, 27 May 2017, hereinafter Makino in the IDS) as applied to claims 1-2 and 4-15 above and further in view of Pan et al. (A novel mutation in LAMIN A/C is associated with isolated early onset atrial fibrillation and progressive atrioventricular block followed by cardiomyopathy and sudden cardiac death, 01 May 2010, hereinafter Pan).
The teachings of Fang, Tintelen and Makino are set forth in the obviousness rejection above and incorporated herein by reference.
Regarding instant claim 3, the combined teachings of Fang, Tintelen and Makino render the method of instant claim 1, prima facie obvious. Fang, Tintelen and Makino do not teach wherein the LMNA mutation results in lamin A/C haploinsufficiency and abnormal activation of the PDGFR signaling pathway.
Pan teaches a novel LMNA mutation present in a large family affected with cardiac disease (Pg. 2, first full paragraph). Pan teaches the family presented a phenotype of early-onset atrial fibrillation (AF) and progressive atrioventricular block (AVB) that is followed by dilated cardiomyopathy (DCM) and sudden cardiac death (SCD) (Pg. 2, continued paragraph). Pan teaches the mutation as a frameshift mutation at codon 117 involving a heterozygous insertion of a guanine between nucleotides 348 and 349 (K117fs) (Pg. 3, first full paragraph; Figure 1C). Pan teaches the K117fs as a potentially lethal LMNA mutation that leads to DCM with high risk of SCD (Pg. 2, second full paragraph; Pg. 4, first full paragraph). Pan teaches the mutant (K117fs) in the study population caused a much larger than expected decrease in wildtype mRNA and protein levels than would be predicted by haploinsufficiency (Pg. 4, continued paragraph) (this strongly suggests that the mutation results in at least some, and likely a severe form of, haploinsufficiency, along with other potential mechanisms).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, in view of the teachings of Fang, Tintelen, Makino and Pan, to have modified the method of Fang to more specifically treat a subject afflicted with dilated cardiomyopathy, wherein the subject is identified to have a K117fs LMNA mutation, with a reasonable expectation of success. The motivation being to prevent sudden cardiac death (SCD) increasingly being recognized as a manifestation of LMNA mutations (Pg.3, fourth full paragraph).
In the absence of evidence to the contrary, a PHOSITA would have reasonably expected that the method of Fang, when practiced in a method of treatment of dilated cardiomyopathy in a subject identified to have a K117fs LMNA mutation, would necessarily result in lamin A/C haploinsufficiency and abnormal activation of PDGFR signaling due to the mutation.
Double Patenting - Maintained
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-15 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 and 4-14 of co-pending Application No 18/132,919 in view of Fang et al. (WO 2019/233469 A1, publication date 12 December 2019, hereinafter Fang in the IDS).
Although the claims at issue are not identical, both sets of claims are drawn to a method of treating dilated cardiomyopathy due to an LMNA mutation.
The instant claims are drawn to a method for treating and/or preventing dilated cardiomyopathy due to an LMNA mutation, the method comprising: administering to a subject a therapeutically effective amount of an inhibitor of PDGF signaling, wherein the inhibitor of PDGF signaling is crenolanib or salt thereof (instant claim 2) or wherein the inhibitor of PDGF signaling is Imatinib; Sunitinib; Sorafenib; Pazopanib; Nilotinib; Cediranib; Motesanib; Axitinib; Linifenib; Dasatinib; Quizartinib; or Ponatinib (instant claim 15).
The claims of the co-pending Application No 18/132,919 are drawn to a method of treating dilated cardiomyopathy in a subject, comprising concomitant administration to the subject of a therapeutically effective amount of: (a) a tyrosine kinase inhibitor; and (b) a Statin; where the tyrosine kinase inhibitor is axitinib, cediranib, crenolanib, dasatinib, imatinib, linifenib, motesanib, nilotinib, pazopanib, ponatinib, quizartinib, sorafenib, or sunitinib (claim 2 of reference ‘919 application); where the subject has a mutation in either or both of the subject’s lamin A and filamin C proteins (claims 4-14 of reference ‘919 application).
Regarding the limitation drawn to “an inhibitor of PDGF signaling” of the instant claims, the tyrosine kinase inhibitors recited in claim 2 of the reference ‘919 application are identical to the inhibitors recited by instant claims 2 and 15.
According to MPEP 2112.01(II), “Products of identical chemical composition can not have mutually exclusive properties.” Any properties exhibited by or benefits from are not given any patentable weight over the prior art provided the composition is inherent. A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the disclosed properties are necessarily present. In re Spada, 911 F.2d 705, 709, 15 USPQ 1655, 1658 (Fed. Cir. 1990). Therefore, the tyrosine kinase inhibitors of the reference application are capable of functioning as an inhibitor of PDGF signaling, by virtue of their inherent property. Claims 1-2 and 4-14 of reference application anticipate instant claims 1-2 and 15.
The reference ‘919 application does not teach the limitations of instant claims 3-14.
Fang teaches a method of treating and/or preventing a disease by administering an effective amount of crenolanib or a pharmaceutically acceptable salt thereof to a patient (Para. [0076]; Claim 13; Paras. [0051]-[0052]). Fang teaches the administration of 50 mg to 500 mg per day, 100 to 450 mg per day, 200 to 400 mg per day, 300 to 500 mg per day, 350 to 500 mg per day, or 400 to 500 mg per day of crenolanib (Para. [0077]; Claim 13). Fang teaches suitable pharmaceutically acceptable salts to include inorganic and organic acid addition salts such as hydrochloride, phosphate, acetate, citrate, p-toluenesulfonate (Para. [0117]). Fang teaches the PDGFR signaling inhibitor is administered orally, intravenously, intramuscularly, intraarterially, intramedullarily, intrathecally, intraventricular, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual or rectal administration (Para. [0074]; Claim 12). Fang teaches crenolanib was administered twice on the second and fourth day of therapy (Para. [0189]). Fang teaches the exact dosage will be determined by the physician based on factors related to the subject in need of treatment (Para. [0075]).
According to MPEP 2144.05(II)(A), "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Therefore, it would have taken no more than the relative skills of one of ordinary skill in the art through routine experimentation to have arrived at the optimal administration schedule and duration of treatment, absent any criticality of the times of administration.
Regarding the limitations as in instant claims 4-9, they are related to the mechanism of action of the agent, an inhibitor of PDGF signaling, used in the treatment of dilated cardiomyopathy due to an LMNA mutation. The reference ‘919 application in view of Fang, teaches the active step of administering the same agent, that acts as an inhibitor of PDGF signaling, to the same patient population, a subject afflicted with dilated cardiomyopathy associated with a mutation in either or both of the subject’s lamin A and filamin C proteins (i.e., an LMNA mutation). Therefore, practicing the method of the reference ‘919 application in view of Fang in appropriate dosages, would have necessarily resulted in the same treatment effects, rendering the limitations of instant claims 4-9 prima facie obvious.
The teachings of the reference ‘919 application in view of Fang render obvious the limitations of instant claims 3-14.
Therefore, instant claims 1-15 and claims 1-2 and 4-14 of co-pending Application No 18/132,919 are not patentably distinct.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicants argue on pages 5-6 of the response dated 12/18/2025, that “As set forth in the MPEP (underlining added): lf a provisional nonstatutory double patenting rejection is the only rejection remaining in an application having the earlier patent term filing date, the examiner should withdraw the rejection in the application having the earlier patent term filing date and permit that application to issue as a patent, thereby converting the provisional nonstatutory double patenting rejection in the other application into a nonstatutory double patenting rejection upon issuance of the patent.”
Applicant's arguments have been fully considered but they are not persuasive.
Withdrawal of the nonstatutory double patenting rejection will be considered when it is the only rejection remaining and the claims are otherwise allowable. Currently, the claims stand rejected over the combined teachings of Fang, Tintelen, Makino and Pan.
Conclusion
Claims 1-15 are rejected.
Claims 1-2 and 5-9 are objected to.
No claims are allowed.
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/PADMAJA S RAO/Examiner, Art Unit 1627
/Kortney L. Klinkel/Supervisory Patent Examiner, Art Unit 1627